RAS Mutations in ctDNA and Anti-EGFR reINTROduction in mCRC (RASINTRO)

Metastatic Colorectal Cancer Clinical Trial

— RASINTRO  

Official title:

Predictive Impact of RAS Mutations in Circulating Tumor DNA for Efficacy of Anti-EGFR Reintroduction Treatment in Patients With Metastatic Colorectal Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03259009
• Other study ID #: RASINTRO
• Status: Not yet recruiting
• Phase: N/A
• First received: August 14, 2017
• Last updated: September 7, 2017
• Start date: October 1, 2017
• Est. completion date: June 1, 2020

Study information

• Verified date: September 2017
• Source: Association des Gastroentérologues Oncologues
• Contact: Aziz ZAANAN, MD, PhD
• Phone: +33 1 56 09 50 64
• Email: aziz.zaanan[@]aphp.fr
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Some data have suggested a clinical survival benefit related to the reintroduction of anti-EGFRs therapy in patients with metastatic colorectal cancer (mCRC). Based on resistance mechanisms related to the development of resistant clones, the investigators could assume that patients who benefited most from the reintroduction of anti-EGFRs were those who, through interval chemotherapy, had no longer mutated RAS clone in plasma that appeared during the progression with the first anti-EGFR treatment. Conversely, those who did not benefit from this therapy were probably patients who had mutated RAS clones circulating at the time of reintroduction of anti-EGFRs. To support this hypothesis, investigators propose to evaluate the correlation between the eventual presence of RAS mutations in circulating blood and the efficacy of an anti-EGFR therapy reintroduction in patients with mCRC.

Description:

Somatic mutations in KRAS exon 2 are considered as a predictive marker of lack of efficacy for anti-EGFR therapy (panitumumab or cetuximab) in patients with metastatic colorectal cancer. Recently, it has been shown that rare mutations of KRAS (exons 3 or 4) or NRAS (exons 2, 3 and 4) were also predictive for resistance to anti-EGFR antibodies. These data led to a further restriction of anti-EGFR therapy to the subgroup of patients without any RAS mutations.

Emerging RAS mutations in circulating tumor DNA (ctDNA) could be detected in patients with RAS non-mutated colorectal cancer treated with anti-EGFR. The appearance in blood of these rare RAS mutated clones during anti-EGFR therapy was associated with shorter progression free-survival. These results suggest that the growing and development of rare RAS mutated clone, which is probably pre-existing in the primary tumor, may constitute a mechanism of resistance for anti-EGFR therapy.

A phase II prospective study has evaluated the interest of reintroduction of cetuximab in 39 patients previously treated with irinotecan and cetuximab. For inclusion, patients should have had a clinical benefit (stable disease for at least 6 months or clinical response) with the previous line of cetuximab plus irinotecan therapy and then a progression disease for which underwent a new line of chemotherapy before the rechallenge of cetuximab plus irinotecan. The median number of line of chemotherapy before inclusion was 4, and the median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. In this study, the overall response rate was 53.8%, and the median progression free-survival was 6.6 months. No evaluation of circulating tumor DNA was performed in this study.

These data indicate that the colorectal cancer genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockage. It seems that efficacy of anti-EGFR reintroduction could be specifically observed in subgroup of patients who no longer have a RAS mutated clone following the interval chemotherapy.

The aim of this prospective non-interventional study is to evaluate the predictive impact of RAS mutations in circulating tumor DNA for efficacy of anti-EGFR reINTROduction (RASINTRO study) treatment in patients with metastatic colorectal cancer.

The primary endpoint will be the correlation between RAS mutations status in circulating tumor DNA and progression-free survival from the reintroduction of anti-EGFR therapy.

The blood sample for circulating tumor DNA assessment will be carried out in patients who agreed to participate in this observational study just before the first 3 cycles of chemotherapy. This study does not require any additional invasive procedures to those already scheduled for routine care. Indeed, blood sample will be collected from the Huber needle previously implanted in the port-a-cath for chemotherapy perfusion.

After DNA extraction from bood samples, RAS mutation testing will be performed using sequencing with a panel of genes (Ion AmpliSeq Colon and Lung Cancer Panel).

The data related to the patient (age at diagnosis, sex, weight, height, WHO performance status), tumor (tumor markers CEA and CA 19-9, histological type and tumor differentiation, tumor stage, and metastatic sites) and treatment (resection of the primary tumor, date of surgery, lines of chemotherapy, protocol regimen) will be collected anonymously. Monitoring data concern the efficacy of chemotherapy (tumor response, the date of disease progression/death).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 73
• Est. completion date: June 1, 2020
• Est. primary completion date: January 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 years

• Metastatic colorectal cancer histological confirmed without somatic mutations of KRAS (exons 2, 3 et 4) and NRAS (exons 2, 3 et 4)

• Apart from contraindication, patients should have already received fluoropyrimidine, irinotecan, oxaliplatin, anti-EGFR (panitumumab or cetuximab) and anti-angiogenic (bevacizumab or aflibercept) therapies

• Previous treatment with anti-EGFR-based chemotherapy (panitumumab or cetuximab) should have provided an objective tumor response (according to RECIST 1.1 criteria) and/or PFS = 4 months.

• At least one line of interval chemotherapy between the last cycle of anti-EGFR based treatment and reintroduction of anti-EGFR therapy

• Signed written informed consent obtained prior to any study specific screening procedures

Exclusion Criteria:

• Discontinuation of first anti-EGFR therapy for other reasons than tumor progression

• Previous malignancy other than colorectal cancer in the last 5 years

• Medical, sociological, psychological or legal conditions that would not permit the patient to sign the informed consent

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Locations

Country	Name	City	State
n/a

Sponsors (8)

Lead Sponsor	Collaborator
Association des Gastroentérologues Oncologues	Hôpital Européen George Pompidou, APHP, Paris, France, Methodology and Quality of Life in Oncology Unit, Besançon University Hospital, France, Pitié-Salpêtrière Hospital, Poitiers University Hospital, Poitiers, France, Rennes University Hospital, Rennes, France, UMR-S1147, Université Paris Descartes, University Hospital Robert Debré, Reims, France

References & Publications (11)

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1;26 — View Citation

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Blasinska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panit — View Citation

Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Blasinska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of — View Citation

Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal can — View Citation

Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, S — View Citation

Morelli MP, Overman MJ, Dasari A, Kazmi SM, Mazard T, Vilar E, Morris VK, Lee MS, Herron D, Eng C, Morris J, Kee BK, Janku F, Deaton FL, Garrett C, Maru D, Diehl F, Angenendt P, Kopetz S. Characterizing the patterns of clonal selection in circulating tumo — View Citation

Norton SE, Lechner JM, Williams T, Fernando MR. A stabilizing reagent prevents cell-free DNA contamination by cellular DNA in plasma during blood sample storage and shipping as determined by digital PCR. Clin Biochem. 2013 Oct;46(15):1561-5. doi: 10.1016/ — View Citation

Santini D, Vincenzi B, Addeo R, Garufi C, Masi G, Scartozzi M, Mancuso A, Frezza AM, Venditti O, Imperatori M, Schiavon G, Bronte G, Cicero G, Recine F, Maiello E, Cascinu S, Russo A, Falcone A, Tonini G. Cetuximab rechallenge in metastatic colorectal can — View Citation

Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C, Lamba S, Hobor S, Avallone A, Valtorta E, Rospo G, Medico E, Motta V, Antoniotti C, Tatangelo F, Bellosillo B, Veronese S, Budillon — View Citation

Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastati — View Citation

Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Ma — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	PFS will be evaluated according to the RAS mutations on circulating tumor DNA status	Time from the date of beginning the reintroduction of anti-EGFR therapy to date of tumor progression or death from any cause, whichever occurred first, assessed up to 6 months.
Secondary	Tumor response	Tumor response will be evaluated according to the RAS mutations on circulating tumor DNA	The tumor response will be assessed in patients with measurable lesions according to RECIST criteria version 1.1, assessed up to 6 months
Secondary	Overall survival (OS)	OS will be evaluated according to the RAS mutations on circulating tumor DNA	Time from the date of beginning the reintroduction of anti- EGFR therapy to date of death of any cause, through study completion, an average of 1 year